title: Brain pharmacokinetics of neurotoxin-loaded PLA nanoparticles modified with chitosan after intranasal administration in awake rats.
abstract: BACKGROUND
  Neurotoxin (NT), an analgesic peptide which was separated from the venom of Naja naja atra, is endowed an exceptional specificity of action that blocks transmission of the nerve impulse by binding to the acetylcholine receptor in the membrane. However, it has limited permeability across the blood-brain barrier (BBB).
  
  
  OBJECTIVE
  The purpose of this study was to encapsulate NT within polylactic acid (PLA) nanoparticles (NPs) modified with chitosan (NT-PLA-cNPs) and to evaluate their brain pharmacokinetic behaviors after intranasal (i.n.) administration using a microdialysis technique in free-moving rats.
  
  
  METHODS
  NT-PLA-cNPs (NT labeled with fluorescein isothiocyanate) were prepared and characterized. Then, NT-PLA-cNPs were i.n. administered to rats and the fluorescence intensity in the periaqueductal gray (PAG) was monitored for up to 480 min, with NT-PLA-NPs and NT solution as control groups.
  
  
  RESULTS
  The NPs prepared were spherical with a homogenous size distribution. The mean particle size, zeta potential, and entrapment efficiency were 140.5 ± 5.4 nm, +33.71 ± 3.24 mV, and 83.51 ± 2.65%, respectively. The brain transport results showed that Tmax of NT-PLA-cNPs was equal with that of NT-PLA-NPs after i.n. administration (150 min). The Cmax and AUC(0-8 h) of each group followed the following order: NT-PLA-cNPs > NT-PLA-NPs. The corresponding absolute bioavailability (Fabs) of NT-PLA-cNPs was about 151% with NT-PLA-NPs as reference preparations.
  
  
  CONCLUSIONS
  These results suggest that NPs modified with chitosan have better brain targeting efficiency and are a promising approach for i.n. delivery of large hydrophilic peptides and proteins in improving the treatment of central nervous system (CNS) disorders.
authors.affiliation: College of Pharmaceutical Science, ZheJiang Chinese Medical University , HangZhou , China.
authors.forename: Xingguo
authors.initials: X
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.forename: Guobao
authors.initials: G
authors.lastname: Chai
authors.forename: Xiangyi
authors.initials: X
authors.lastname: Zhang
authors.forename: Fanzhu
authors.initials: F
authors.lastname: Li
mesh_terms: D000281:Administration, Intranasal; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D048271:Chitosan / Q000737:chemistry*; D003039:Cobra Neurotoxin Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004339:Drug Compounding; D016503:Drug Delivery Systems; D005456:Fluorescent Dyes / Q000737:chemistry; D006207:Half-Life; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D017551:Microdialysis; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism*; D011091:Polyesters; D011108:Polymers / Q000737:chemistry; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013499:Surface Properties; D014018:Tissue Distribution
chemical_list: D018712:Analgesics, Non-Narcotic; D003039:Cobra Neurotoxin Proteins; D005456:Fluorescent Dyes; D011091:Polyesters; D011108:Polymers; D019344:Lactic Acid; C033616:poly(lactide); D048271:Chitosan